US3894037A

US3894037A - Certain isothiocyanobenzimidazoles

Info

Publication number: US3894037A
Application number: US491585A
Authority: US
Inventors: Paul Brenneisen; Thomas Wenger; Jean-Jacques Gallay; Wolfgang Schmid
Original assignee: Ciba Geigy Corp
Current assignee: Novartis Corp
Priority date: 1971-05-24
Filing date: 1974-07-24
Publication date: 1975-07-08
Anticipated expiration: 1992-07-08

Abstract

New isothiocyanobenzazoles, process for the production and compositions containing these isothicyanobenzazoles having anthelminthic activity in warm blooded animals.

Description

United States atent Brenneisen et a1.

Italy a, 1975 CERTAIN ISOTHIOCYANOBENZIMIDAZOLES Inventors: Paul Brenneisen, Basel; Thomas Wenger, Riehen, Basel; Jean-Jacques Gallay, Magden, Aayau; Wolfgang Schmid, Neuallschwil, all of Switzerland Assignee: Ciba-Geigy Corporation, Ardsley,

N.Yr

Filed: July 24, 1974 Appl. No.: 491,585

Related US. Application Data Division of Ser. No. 255,334, May 22, 1974, Pat. No. 3,840,550.

Foreign Application Priority Data May 24, 1971 Switzerland 7542/71 11.8. C1. 260/3092 Int. Cl C07d 49/38 Field of Search 260/3092 OTHER PUBLICATIONS Brenneisen et a1. Chem. Abst. 1969, Vol. 71, No. 61372k, QD1.A51. Teruya et a1. Chem. Abst. 1966, Vol. 64, Columns 5069-5070, ODLASI.

Primary Examiner-Natalie Trousof Attorney, Agent, or FirmFrederick H. Rabin [57] ABSTRACT New isothiocyanobenzazoles, process for the production and compositions containing these isothicyanobenzazoles having anthelminthic activity in warm blooded animals.

13 Claims, No Drawings QERTAHN llSUTHl OCYANUBENZTMHDAZOLES This is a division of application Ser. No. 255,334, filed on May 22, 1974, now US. Pat. No. 3,840,550. The present invention relates to new isothiocyanobenzazoles, to processes for their production, as well as to anthelmintic agents containing these new isothiocyanobenzazoles as active substance.

Among the endoparasites to be found in warmblooded animals, the helminthes, in particular, are ones causing a great deal of harm. Thus, for example, the infestation of animals by worms leads not only to a retardation in growth, but also to the frequent occurrence of damage so severe that it can result in the death of the affected animals. It is therefore of the greatest importance that agents be developed which are suitable for the control of helminthes and of their development stages, as well as for the prevention of infestation by these parasites. A number of substances having anthelmintic action have become known; but frequently these are not able, however, to fully satisfy the requirements: either they have an inadequate effect in compatible doses with undesirable side-effects, however, in the case of therapeutically effective doses, or they possess too narrow a range of action. For example, d,l- 2,3,5,6-tetrahydro-6-phenyl-imidazo-[2,l-5]thiazo1e, known from the Dutch Pat. No. 6,505,806, is effective only against nematodes, but not against trematodes and cestodes. ln addition, isothiocyanobenzazole derivatives having anthelminthic activity are known from the Belgian Pat. No. 599,413.

In the present description the term helminthes applies to nematodes, cestodes and trematodes; in particular, therefore, to worms of the gastrointestinal tract, of the liver and of other organs.

The new anthelmintically effective isothiocyanobenzazoles correspond to the general formula 1'.

swag a,

wherein each of the substituents R to R and/or each of the substituents R to R represent the isothiocyano group, and the remaining substituents of the benzene nucleus A independently represent hydrogen, halogen, nitro, hydroxy, alkyl, alkoxy, halogenalkyl, and those of the benzene nucleus B each independently represent hydrogen, halogen, nitro, cyano, alkyl, alkoxy, halogenalkyl, alkylamino, dialkylamino, alkanoylamino, phenyl, or two substituents in the ortho-position with respect to each other represent a benzene nucleus bound to the nucleus B,

X represents oxygen, sulphur, or the group l lR wherein R represents hydrogen, alkyl, alkenyl, alkanolyl, alkyl substituted by benzoyl or halogenated benzoyl, benzene optionally substituted by halogen, or phenyl or benzyl optionally substituted by alkyl,

Y represents oxygen, sulphur, or the group NR' wherein R represents hydrogen, alkyl or alkenyl,

Z represents a straight-chain or branched alkylene bridge member, and

n represents the number 0 or 1, with the proviso that, among the radicals R to R the isothiocyano groups are, in each case, only in the mor p-position to hydroxy or alkylamino groups, and that, if Y represents the Ni l-group and n equals 0, the substituents R and R do not represent isothiocyano, as well as their addition salts and quaternary salts nontoxic in anthelmintically effective doses for the organism of warm-blooded animals.

Y is preferably oxygen, sulphur, the group NH or The aliphatic bridgemember Z is preferably ethylene or vinylene.

The above mentioned substituents R and R of the groups N1R and l l-R', respectively, represents in preferred compounds of the general formula I: hydrogen or alkyl.

The alkyl radicals mentioned in the above definition of the substituents of the general formula 1 preferably contain 1 to 4 carbon atoms; the correspondingly defined alkenyl radicals preferably 3 or 4 carbon atoms.

Suitable non-toxic salts of compounds of the general formula 1 are preferably the acid addition salts nontoxic in anthelmintically effective doses for the organism of warm-blooded animals.

By addition salts are preferably meant the salts of the following inorganic and organic acids: hydrohalic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulphuric acid, fluoboric acid (HBF perchloric acid, alkylsulphuric acid such as methylor ethylsulphuric acid, naphthoic acids, benzoic acid, halogenobenzoic acids, acetic acid, halogenoacetic acids such as trichloroacetic acid, aminoacetic acid, propionic acid, halogenopropionic acids, butyric acid, lactic acid, stearic acid, aliphatic dicarboxylic acids such as oxalic acid, tartaric acid, maleic acid, aromatic sulphonic acids such as p-toluenesulphonic acid, etc.. Such inorganic and organic acids are likewise suitable for the formation of quaternary salts of the pyrimidine derivatives of formula I wherein R and/or R represent a trialkylammonioalkyl radical.

The new isothiocyanobenzazoles of formula I are produced according to the invention by the reaction of an aminobenzazole of formula 11:

wherein each one of the substituents R to R and/or each one of the substituents R to R represent(s) the amino group, and the remaining substituents of the benzene nucleus A each independently represent hydrogen, halogen, nitro, hydroxy, alkyl, alkoxy, halogezene nucleus bound to the nucleus B, and the symbols X, Y, Z and n have the meanings given under the formula l, with the proviso that, among the radicals R to R the amino groups are, in each case, only in the mor p-position with respect to hydroxyor alkylamino groups, and that, if Y denotes the Nl-l-group and n equals 0, the substituents R and R do not represent amino, the said reaction being performed with a reagent capable of converting the amino groups into isothiocyanato groups, preferably in the presence of a solvent or diluent inert to the reactants;

Suitable reagents capable of introducing a thiocarbonyl group in the process according to the invention are given below:

a. a thiocarbonic acid derivative of the general formula ll:

Hal CS Y wherein Hal represents chlorine or bromine, and

Y represents chlorine, bromine, or a dialkylamino group,

and by which definition is preferably meant thiophosgene, which is optionally reacted in the presence of an acid-binding agent at temperatures of between and 75, and N,N-diethylthiocarbamoyl chloride, which is reacted at temperatures of between 40 and 200;

b. a bis-thiocarbamoylsulphide of the general formula Ill:

/\lkyl N 211331 (11 S Alkyl wherein the index In represents the number 1 or 2, and alkyl preferably denotes ethyl, in the presence of hydrogen halide;

c. pentathio-dipercarbonic acid-bis-trichloromethy ester; 7

d. ammonium rhodanide in the presence of gaseous l-lCl;

e. phosgene and phosphorus pentasulphide;

f. carbon disulphide in the presence of an inorganic or organic base; the amino group is firstly converted into the dithiocarbamic acid salt, which is then dehydrosulphated to the isothiocyano group;

g. ammonium rhodanide and benzoyl chloride, and thermal decomposition of the intermediate thiourca to the isothiocyano derivative;

h. carbon disulphide and dicyclohexylcarbodiimide in the presence of a tertiary amine.

i'. The new isothiocyanobenzazoles of formula I can also be obtained by aprocess in which, instead of amine, a corresponding nitro, nitroso, azo or azoxy compound is reacted under pressure 1. with carbon disulphide, carbon oxysulphide, or

mixtures of carbon disulphide and carbon oxysulphide, in the presence of potassium hydrogen sul- Pharm. 295, 146- 151 (1962); the reaction with N,N-diethylthiocarbamoyl chloride is carried out according to org. Chem. 30, 2465 (1965); that with bis-thiocarbamoylsulphides according to F.1-l. Marquardt, Helv. Chim. Acta, 49, 1716 (1966), that with pentathiodipercarbonic acid-bistrichloromethyl ester according to R. Gottfried, Angew. Chem. (Applied Chem.) 78,985 (1966), that with ammonium rhodanide and HCl gas according to the British Pat. No. 1,099,768, and the reaction with phosgene and phosphorus pentasulphide according to l-louben-Weyl, 4th Edition, Vol. 9, p. 867 onward. The dehydrosulphation following the reaction with carbon disulphide and bases can be performed oxidatively with metal salts (British Pat. No. 793,802, Dutch Pat. No. 81,326); it can be performed, e.g. with lead-, copper-, zincor iron-III- salts, iodine, alkali metal hypochlorites or -chlorites, preferably with sodium and potassium salts (French Pat. No. 1,311,855), also with suitable acid halides such as with phosgene and phosphorus oxychloride [D. Martin et al., Chem. Ber. 98, 2425-2426 (1965)], as well as with C1 and ammonium sulphide (German Auslegeschrift No. 1,192,189), or chloroamine T (British Pat. No. 1,024,913).

The reaction with ammonium rhodanide and benzoyl chloride, which firstly leads to the thiourea derivative which is converted by heating, e.g. in boiling chlorobenzene, into the isothiocyano derivative, is performed, for example, according to Houben-Weyl, 4th Edition, Vol. 9, page 867 onward; and the reaction with carbon disulphide and dicyclohexylcarbodiimide, in the presence of a tertiary amine, is carried out according to J.C. Jochims, Chem. Ber. 101, 1746 (1968) Examples of inert solvents or diluents which can be used in theprocess according to the invention are as follows:

aliphatic and aromatic hydrocarbons,

' aliphatic and aromatic halogenated hydrocarbons,

ethers and ethereal compounds, ketones, amides such as dimethylformamide, etc., water, or mixtures of such solvents with water.

The benzazole compounds embraced by formula 11 wherein X stands for the group NH can be converted by reaction with conventional acylating, alkylating or alkenylating agents into the corresponding derivatives.

The amines serving as starting materials may be'used in the form of the free bases, and also as addition salts with acids, particularly with mineral acids.

The jaminobenzazoles embraced by formula II and serving as starting materials are, in some cases, de-

scribed in the literature; or they can be produced by known processes, e.g. by catalytic hydrogenation, or by the Bechamp reduction of the corresponding nitro compounds which can be obtained, amongst other means, by nitration of suitable benzazoles (cp. Houben-WeyLMuller, Methods of Organic Chemistry, Vol. Xl/l, 1957).

The production of such nitrobenzazoles is generally known. Nitrosubstituted Zanilinobenzimidazoles can be obtained, for example, by the reaction of phenylor p-chlorophenylcarbonimidoyl-dichloride with ophenylenediamines substitued by nitro groups (cp. ,l.org.Chem. 29, 1613-1615, 1964). 5,4-Dinitrolanilinobenzothiazole can be produced from s-di-pnitrophenylthiocarbamide with ring formation by the action of bromine, and a subsequent reducing treatment (see J.Chem.Soc. 1929, 464. Suitable benzazoles, which are substituted on the aromatic nuclei with sulphonamide groups, can also be subjected to hydrolysis, whereby the corresponding aminobenzazoles are obtained. Furthermore, various processes have already been described for the production of the aminobenzazoles to be used as starting materials in the process according to the invention in which processes the starting compounds are 2-halogenbenzazoles; these are reacted with suitably substituted phenols, thiophenols or anilines to give the corresponding 2- phenoxybenzazoles (cp. French Pat. No. 1,242,962, Chemical Abstracts 55, 21928 a), phenylthiobenzazoles (cp. J.Chem.S0c.(l3) 1968, 1280-1284), or anilinobenzazoles (Ann. Chimica 44, 3l0, 1954; Helv.Chim.Acta 44, 12731282, 1961 Compounds of the type l-aminoalkyl-Z-anilinobenzimidazoles can be produced by the ring-closure reaction of 2- (alkylaminoalkylamino)anilines with S- methylisothioureas (cp. US. Pat. No. 3,000,898).

According to a type of reaction not hitherto described, substituted benzimidazoles corresponding to formula II can be obtained which, according to the invention, can be used as starting materials for the present invention. For this purpose, a suitably substituted 2-halogenbenzimidazole of the formula:

2 ilal R R 4 R wherein the radicals R to R each independently represent hydrogen, halogen, nitro, hydroxy, amino, alkyl, alkoxy, or halogenalkyl, and the radical R represents hydrogen, alkyl, alkenyl, alkanoyl, alkyl substituted by benzoyl or halogenated benzoyl, benzoyl optionally substituted by halogen, or phenyl or benzyl optionally substituted by alkyl, and Hal denotes halogen, preferably chlorine, is reacted with an aminophenol of the formula:

wherein the radicals R to R each independently represent hydrogen, halogen, nitro, cyano, alkyl, alkoxy, halogenalkyl, amino, alltylamino, dialltylamino, alkanoylamino, phenyl, or two substiuents in the orthoposition with respect to each other represent a bound benzene nucleus, and the amino group is preferably in the mor p-position with respect to the hydroxy group. The reaction is performed in the presence of a strong base (KOH, NaOl l), preferably in an equimolar amount with respect to the benzimidazole. On the other hand, the aminophenol is present in excess, preferably in an excess of 2 moles per mole of benzimidazole. The reaction is performed at 145C, with separation by distillation of the formed water. The produce essentially obtained with o-aminophenol is 2-(1 hydroxyanilino)-benzimidazoles.

On account of their excellent anthelmintic activity, the new isothiocyanobenzazoles of the following formula Ill:

wherein the radicals R R R R and R as well as the symbols Y, Z and n, have the meanings given under formula l, with account being taken of the defined exceptions, whereby the isothiocyano group in the nucleus A is in the 5- or 6-position, and/or that in the nucleus B in the 2(o)-, 3(m)- or 4'(p)-position with respect to the bridge member, are of particular importance.

The benzazole compounds according to the invention and their salts display a pronounced anthelmintic action against the most important nematodes infesting animals and human beings (e.g. ascaridae, trichostronglidae, ancylostomatidae, strongylidae), cestodes (e.g. anoplocephalidae, taeniidae) and trematodes (e.g. fasciolidae, schistosomidae). The control of helminthes is of special significance in the case of domestic animals and productive livestock, such as, e.g. cattle, pigs, horses, sheep, goats, dogs, cats, as well as poultry. the active substances according to the invention can be administered to the mentioned animals either as single doses or as repeated doses. A better effect is obtained in some cases by a protracted administration of the active substances, or it is possible, in other cases, to obtain the desired effect with smaller overall doses. The active substances, or mixtures containing them, may also be added to the feed or to the water, the active substance concentrations then being between 0.01 and 1%.

The new active substances can be administered to the animals direct, orally or abomasally, in the form of solutions, emulsions, suspensions (drenches), powders, tablets, boluses and capsules, the administration being either in the form of a single dose or in the form of repeated doses. In some cases, a better effect is achieved by a protracted administration, or a lesser amount as an overall dose may suffice. The active substances, or mixtures containing them, can also be added to the feed or to the water, or they may be contained in so-called feed premixtures.

The usual carriers are used for the preparation of the. dosage units, such as kaolin, talcum, bentonite, sodium chloride, calcium phosphate, carbohydrates, cellulose powders, cottonseed meal, carbowaxes, a gelatine, or liquids such as water, optionally with the addition of surface-active substances such as ionic or non-ionic dispersing agents, as well as oils and other solvents harmless to the organism of animals. If the anthelmintic agents are in the form of feed concentrates, then suitable carriers are, e.g. productive feeds, fodder grain or protein concentrates. Such feed concentrates may contain, in addition to the active substances, additives, vitamines, antibiotics, chemotherapeutics, bacteriostatics, fungistatics, coccidiostatics, hormone preparations, substances with an anabolic action, or other substances promoting growth, or improving the quality of the meat of slaughter cattle, or useful in some other way for the organism of animals.

Suitable dosage units for oral administration, such as dragees or tablets, preferably contain 100 to 500 mg of 20 the active substance according to the invention, that is, 20 to 80% of a compound of the general formula I. The dosage units are produced by the combining of the acln t he; following are described certain tests carried out to determine the anthelmintic activity of the new benzazoles of the general formula I.

Determination of th'e'a'nth elmintic activity on fowl l 1 infested with Ascaridia galli. I

Oneto three-day old chickens wereartificially infested with eggs of Ascaridia galli (ascarids). Groups each of five chickens ,were used for each test. The active substances were administered to the chickens 4 to 5 weeks after infestation, the administration being in the form of a single dose per day on 3 successive days. Unfested chickens which had not been treated with the active substances were taken as a control.

Evaluation:

The number of Ascaridia galli discharged by each test group in the course of 5 days after the first administration of the active substance was determined daily, and also the number found on examination of the 5th test day in the intestines. Furthermore, the number of chickens free from worms was determined daily No. of Ascaridia dose galli from 5 chicks No. of General 7 mg/kg worm-free Active substance of body discharged found chickens condiweight during duration on tion of test dissabsolin of ection ute No total No 2-Phenoxy-6-isothiocyano-l .3-benzothiazole 750 108 100 good 2-(3'-Chlorophenoxy)-6-isothiocyano- 1,3-benzothiazole 750 219 100 0 5 good 2-(2'Chlorophenoxy)-6-isothiocyano-l ,3-benzothiazole 750 6] lOO 0 5 good 2-(4'-Fluorophenoxy)-6-isothiocyanol ,3-benzothiazole 750 l l 3 100 O 5 good 2-(4'-Methylphenoxy)-6-isothiocyanol ,3-benzothiazole 750 60 100 0 5 good 2-(3-Methoxy-phenoxy)-6-isothiocyanol ,3benzothiazole 750 l 16 100 O 5 good 2-(2'-Fluorophenoxy)-6-isothio 750 80 I00 0 5 good cyano-l ,3-benzothiazole l-Methyl-2-( p-isothiocyanophenylthio(-benzimidazole-chlorohydrate 750 l 82 I00 0 5 good 2-( 3 -lsothiocyanophenoxy I -methylben zimidazole-hydrochloride 750 23 l 96 8 3 good tive substance with, for example, solid pulverulent carriers such as lactose, saccharose, sorbitol, mannitol, starchessuch as potato starch, maize starch or amylopectin, also laminaria powder or citrus pulp powder, cellulose derivatives or gelatine, optionally with the addition of lubricants such as magnesium or calcium stearate, or polyethylene glycols, to form tablets or dragee cores. The last-mentioned are coated with, eg concentrated sugar solutions which can also contain, e.g. gum arabic, talcum and/or titanium dioxide; or with a lacquer dissolved in readily volatile organic solvents or solvent mixtures. It is also possible to add dyestuffs to these coatings, eg for the identification of the various doses of active substance.

Tests on mice infested by Hymenolepsis nana The active substance were administered in the form of a suspension by means of a stomach probe to white mice artificially infested with Hymenol epis nana. Five animals were used per test. The active substances were administered once daily to each group of animals on 3 successive days. The animals were killed and dissected on the 8th day after commencement of the treatment.

After dissection of the test animals, an evaluation was made by a count of the tapeworms present in the intestines. Untreated mice which had been infested at the same time and in the same manner served as a control.

The agents were well tolerated by the mice and no resulting symtoms were observed.

Daily Infestation Infestation of Active substances dose of the 5 the control mice mg/kg of test'mice on dissection body on dissecweight tion 2-(m-lsothiocyano-phenylamino)-benzoxazole 750 0-0-0-0-0 2 7 l l l9 24 2-Phenoxy-6-isothiocyano-l,3-benzothiazole 7S0 O-O-O-O-O l0 l2 l4 l7 22 2-(4'-lsothiocyano-phenoxy)-6-isothiocyano- 750 O-O-OO-O l2 l5 l6 l9 25 l ,3-benzothiazole' 750 0-0-0-0-2 l2 l5 l6 l9 25 2-( 3'-Chlorophenoxy)-6-isothiocyanol ,3-benzothjazole C ontmued Daily Infestation Infestation of Active substances dose of the the control mice mg/kg of test mice on dissection body on dissecweight tion 2-(4'-Fluorophenoxy)-6-isothiocyano-I,3-benzo- 750 O-O-O-O-i 2 4 5 8 a thiazole 2-(2.3' 5-Trimethyl-phenoxy)-6-isothiocyano- 750 O-O-O-O-O O l 2 2 4 1,3-benzothiazole 2(2'-Methylphenoxy)-6-isothiocyano-l.3-benzo- 750 O-O-O-O-l 3 4 l5 l8 i9 thiazole 2-(4-Methylphenoxy)-6-isothiocyano-l.3-benzo- 750 O-0-O-OO 7 8 l2 l6 2O thiazole 2-(2.4'.5'-Trimethylphenoxy)-6-isothiocyano- 750 O-O-O-O-2 4 5 6 6 l l 1.3-benzothiazole 2-(2"Fluorophenoxy)-6-isothiocyanol.3- 750 O-O-O-O-O 2 6 7 a ll 16 benzothiazole 2-(4-lsothiocyano-phenoxy)-l.3-benzthiazole 750 O-O-O-OO 1O l6 l7 26 33 2-[-lsothiocyano-phenylamino]-5-isothiocyano- 750 O-O-O-O-O ll i2 l2 l6 l6 benzinidazole 2-[4-lsothiocyano-phenylthiol-benzinidazole 750 O-0-O-0-0 l l 2 3 3 2-(3-lsothiocyanophenoxy)-benzimidazole 750 0-0-O-O-l 6 6 l4 l6 2-(4'-lsothiocyanophenoxy)-benzimidazole 750 O-O-0-Ol 2 6 7 l l l6 2(3-lsothiocyanophenoxy)-l-methyl-ben2imi- 750 00-0-00 2 6 7 l1 l6 dazole-hydrochloride 2-(3-lsothiocyanophenoxy)-l-methyl-benzimidazole 750 O-O-O-O-O 3 6 6 7 8 2-(4'lsothiocyano-phenoxy)-l-methyl-benzimi- 750 OO-O-O-O l l l3 l6 23 33 dazole-hydrochloride 2-(4'lsothiocyano-phenylamino)-6-isothiocyano- 750 0-0-0-0-0 4 5 7 8 18 benzoxazole Tests on mice infested by oxyuris The daily dose per animal was 750 mg of active sub- 35 stance per kg of body weight.

The animals were killed and dissected on the 6th day after commencement of the treatment. After dissection 30 of the animals, the evaluation was made on the basis of a count of the mice-oxyuris present in the intestines. Untreated animals which had been infested in the same manner were taken as a control.

Daily dose lnfestat- Infestation of the mg/kg of ion of control animals Active substance body the five on dissection weight test mice 2-(n-lsothiocyano-phenylamino)-benzoxaz0le 750 0-0-0-0-O/ 4/L l; I 3/L/ ll S/L- l 8/L/ 1 ZO/L l 2-Phenoxy-6-isothi0cyano-l ,3-benzthiazole 750 0-0-0-0-0 6/l/./ l/-8/L/l-9/L/ I -l 1/L/ l 9/L/1-1l/L/1 thiazole l3/L/1 2-( 3-Bromophenoxy)-6-isothiocyano-l ,3-benze- 566 O-O-O-O-O lO/L/ll 3/L/l thiazole 2-(4'-fluorphenoxy)-6-isothiocyanol ,3'benze 750 O-O-O-O-O/ 2/L/l-4/L/l-4/L/ l 8/L/l thiazole l I/L/l 2-( 2-Methylphenoxy-6-isothiocyano-l ,3- 750 O-O-O-O-O 8/L/l-8/L/ l l 4/L/ll 5/L/l henzethiazole 20/ L/l 2-(4-Methylphenoxy)-6-isothiocyano-1,3- 750 0-0-0-0-0 4/1-5-8/L/i-3/L/l-8/L/l benzthiazole 2-( 2'-Fluorophenoxy)-6-isothiocyanol ,3- 750 O-O-O-O-O/ O/L- l -3/L- 1 5-24 benzthiazole 2-(4-lsothiocya-no-phenoxy)- l ,3-benzthiazole 750 -5 5/L/l-l0/L/l l3/L/ l 2-4-lsothiocyanatophenoxy)-5-isothiocyano- 750 0-O-0-0 2 4/L/1-5/L/l-5/L/l-6-6/L/l benzimidazole 2-( 2-Methyl-3 '-methoxy-phenoxy )-6-is0thio- 750 0-0-0-0-0 5/L/ l -6-6/l-7- l S/L/l cyanol ,3-benzthiazole 2-( 3'-lscthiocyanophenoxy)- l -methyl-benzimi- 750 0-0-0-0-1 O/L-l-3/L- 1 5-24 dazole-hyd rochloride Tests on rats infested by Fasciola hepatica White laboratory rats are artificially infested with Fasciola hepatica. At the end of the prepatent time, the infestation of the rats by Fasciola hepatica (common liver fluke) was determined by means of 3 successive analyses of the excrement.

12 water forming is continuously distilled off. The mixture is then 'diluted'whilst still hot with 100 ml of dimethylformamide, and poured on to 1500 ml of water. The formed precipitate is filtered off under suction and,

.while still moist, boiled with 400 ml of ethanol with the addition of active charcoal. After filtration, the filtrate is diluted with 400 ml of water and the whole stirred. 2-(3-Aminophenoxy)-l-methylbenzimidazole, M.P. 1 10 to 1 14, precipitates out.

b. An amount of g of thiophosgene, 250 ml of di- Excrement (X3) No. of

The following examples serve to further illustrate the production processes according to the invention. Where not otherwise stated, the term parts denotes parts by weight; the temperatures are expressed in degrees Centigrade.

EXAMPLE i 6-isothiocyano-2-phenoxybenzothiazole An amount of 8.46 g of thiophosgene in a sulphonating flask is stirred into 500 ml of ice water. An addition is then made dropwise, in the course of 10 minutes, of a solution of 18 g of 6-amino-2-phenoxybenzothiazole in 100 ml of dioxane as well as 10 ml of water. The suspension is further stirred overnight at room temperature. The formed precipitate is separated and washed with water; the residue is dissolved in 100 ml of methylene' chloride, and the solution dried over sodium sulphate. After chromatography with methylene chloride through aluminium oxide (neutral, activity stage 11]);

an amount of 12.5 g of 6-isothio cyano- 2- phenoxybenzothiazole, M.P. 118 to 119C, is obtained. r

EXAMPLE 2 2'-( 3 '-isothiocyanophenoxy 1 -methylbenzimidazole The mixture is subsequently heated to 140 to 145 and maintained for 5 hours at this temperature, whilst the- I dose in examination: common General Active substance mg/kg egg discharge liver condition of body before after fluke weight medicamedicatafter tion ion dissection 2-Phenoxy-6-isothiocyano-1,3-benzothiazole 200 positive negative 0 (1- 0 0 good 2-(4'-Fluorophenoxy)-6-isothiocyano-l,3-benz- 200 positive negative 0 0 0 0 good thiazole 2-(2'-Methylphenoxy)-6-isothiocyano-1,3-benz- 200 positive negative 0 0 0 0 good thiazole 2-(2'fluorophenoxy)-6-isothiocyano-1,3-benz- 200 positive negative 0 0 0 0 good thiazo e 2-[4'-lsothiocyano-phenylthio]-benzimidazole 150 positive negative 0 0 0 0 good l-Methyl-2-(p-isothiocyanophenylthio)- 200 positive negative 0 0 0 0 good benzimidazole-chlorhydrate 2-(3'-lsothiocyanophenoxy)-benzimidazole 200 positive negative 0 1 0 0 good hydrochloride 2-(3'-lsothiocyano$henoxy)-l-methyl-benzimi- 200 positive negative 0 0 0 0 good dazolehydrochlori e 2-(3'-lsothiocyanophenoxy)-l-methyl-benz- 200 positive negative 0 0 0 0 good imidazole v 2-(4'-lsothiocyanophenoxy)1-methyl-benz- 200 positive negative 0 0 0 0 good imidazole v 2-(4-lsothiocyanophenoxy)-l-methyl-benz- 200 positive negative 0 0 0 0 good imidazol-hydrochloride 2-(4'-lsothiocyanophenoxy )-benzimidazole 150 i positive negative 0 0,- 0 0 good sulphuric acid salt oxane and ml of water is placed into a sulphating flask and cooled to O to 5; an addition is then made dropwise, within 30 minutes, of a solution of 61 g of 2- (3-aminophenoxy)-l-methylbenzimidazole in 200 ml of dioxane. The mixture is stirred for 3 hours at 0 to 5; it is afterwards further stirred for 15 hours at room temperature. After dilution with 600 ml of water, the precipitate is separated and stirred, for 7 hours at 10, into a solution of 10 g of thiophosgene in 500 ml of acetone. The product is separated and recrystallised from acetonitrile to obtain 29.3 g of (3'- isothiocyanophenoxy 1 -methylbenzimidazolehydrochloride, M.P. 154 to 158C.

6 Parts of this product are treated with a saturated sodium bicarbonate solution.. The obtained base is taken up in chloroform. After drying and distillation of the solution, the residue, recrystallised from cyclohexane, yields 4.2 g of 2-(3-isothiocyanophenoxy)-1- methylbenzimidazole, M.P.: 121 124C.

EXAMPLE 3 (Compound see Example 2) The residue is boiled in cyclohexane. The hot suspension is filtered off, diluted while still hot with petroleum ether, and filtration performed to obtain 2-(3'- isothiocyanantophenoxy 1 -methylbenzimidazo1e, M.P.: l20to 121C.

EXAMPLE 4 2-( 4 -lsothiocyanophenoxy 1 -methylbenzimidazole An amount of 4.8 g of 2-(4-aminophenoxy)-lmethylbenzimidazole is stirred with 2.3 g of bis- (trichloromethane-sulphonyl-trithiocarbonate in 25 ml of water for 24 hours at room temperature. The precipitate is separated, washed with sodium bicarbonate solution, and taken up in chloroform. After drying and distillation of the chloroform solution, the residue is boiled out with cyclohexane, filtered hot, and the filtrate diluted with petroleum ether. The 2-(4'- isothiocyanophenoxy)-l-methylbenzimidazole crystallising out melts at 59 to 61C.

EXAMPLE 5 2-(4-lsothiocyanophenoxy)-1,3-dimethylben zimidazolium-iodide An amount of 14.3 g of 2-(4-isothiocyanophenoxy)- l-methylbenzimidazole is refluxed with 6.8 g of methyl iodide in 50 ml of anhydrous acetone for 21 hours. The solution is then diluted with ether, the precipitate filtered off. and the filtrate concentrated by evaporation to dryness to obtain 16 g of 2-(4- isothiocyanophenoxy )-l ,3-dimethylbenzimidazolium iodide, lVl.P.: 204 to 208C.

EXAMPLE 6 a. A solution of 83 g of p-nitroaniline in 400 ml of dioxane is added at room temperature, with stirring, to 126 g of 2-chloro-o-nitrobenzoxazole obtained from 43.3 g of 2-chlorobenzoxazole with fuming nitric acid (d. 1.52) in sulphuric acid. The solution is heated to 40C and stirred at this temperature for a further 19 hours. The solution is diluted with 200 ml of water; it is then cooled and the precipitate separated. The suction-filter residue is dried and dissolved in 500 ml of dimethylformamide. This solution is purified, and diluted with 200 ml of ethanol. The precipitating 6-nitro-2-(4- nitroanilino)benzoxazole has the melting point 305 to 310C.

b. An amount of 47 g of 6-nitro-2-(4'- nitroanilino)benzoxazole is dissolved in 500 ml of dimethylformamide; and 7 g of palladium charcoal (5%) then added. Within 3 hours at room temperature, 18.6 ml of hydrogen is absorbed. The catalyst is then filtered off, and the filtrate concentrated in a water-jet vacuum at 70C to dryness. The residue is afterwards dissolved with 250 ml of 2-n HCl, and the solution rendered alkaline with concentrated ammonia solution. 6-Amino-2- (4-aminoanilino)-benzoxazole, M.P. 83 to 87, precipitates.

c. A suspension of 17.2 g of 6-amino-2-(4'- aminoanilino)benzoxazole in 200 ml of anhydrous chlorobenzene is saturated at room temperature with hydrogen chloride. An amount of 13.2 g of NH SCN (ammonium thiocyanate) is subsequently added to the mixture. With a further slight introduction of hydrogen chloride, the reaction mixture is refluxed, with stirring, for 6 hours. After cooling, the crystallisate is separated and recrystallised from methyl ethyl ketone. The obtained 6-isothiocyano2-(4'-isothiocyanophenylamino)-benzoxazole has the melting point 233 to 237C.

EXAMPLE 7 2-( 4-Fluorophenoxy )-6-isothiocyanobenzothiazole An amount of 20 g of phosgene is introduced, with ice cooling and with the exclusion of atmospheric mois ture, into ml of o-dichlorobenzene; an addition is then made at 0 of 13 parts of 2-(4'-fluorophenoxy)-6- aminobenzothiazole. The reaction mixture is stirred overnight at room temperature; the temperature is then raised, with a slight introduction of phosgene, within 45 minutes to 90. The flow of phosgene is thereupon stopped, and stirring at continued until the evolution of gas has finished (after ca. 2 hours). After slow cooling to room temperature, 3.75 g of phosphorus pentasulphide is added; stirring with refluxing is subsequently carried out for 14 hours, and the solution filtered off whilst still hot. The filtrate is concentrated by evaporation, and the residue chromatographed through aluminium oxide with methylene chloride as the eluant. The obtained 2-(4-f1uorophenoxy)-6-isothiocyanobenzothiazole has the l\/1.P. 124 126.

EXAMPLE 8 2-( 2 -Fluorophenoxy)-6isothiocyanobenzothiazole An amount of 17 g of ammonium rhodanide is dissolved in 200 ml of absolute acetone; an addition is then made to the solution, with stirring, of 31 g of benzoyl chloride. The reaction mixture is allowed to boil with refluxing for 5 minutes; a solution is then added of 57 g of 2(2-fluorophenoxy)-6-aminobenzothiazole (obtained from 2(2'-fluorophenoxy)-6- nitrobenzothiazole by catalytic hydrogenation, cp. Example 6) in 400 ml of acetone. Stirring is continued for 2 minutes at the boiling temperature, and mixture then poured, with stirring, into 5000 ml of ice water. Filtration is performed, the filter residue washed with water, and suspended in 350 ml of 10% sodium hydroxide solution. The suspension is quickly brought to boiling temperature and allowed to boil for a further 2 minutes. Cooling is then rapidly carried out in an ice bath; the suspension is neutralised with 2-n hydrochloric acid, and the pll-l-value adjusted with 2-n ammonia to 8. Filtration is again performed, the filter residue washed wth water until neutral, and dried at 80 in vacuo. The finely powdered material is suspended in 500 ml of anhydrous chlorobenzene and refluxed for 14 hours. After the solvent has been evaporated off, the residue is chromatographed through aluminium oxide with methylene chloride as the eluant. The obtained 2- (2-fluorophenoxy)-6-isothiocyanobenzothiazole melts at 115 117.

EXAMPLE 9 2-( 4-lsothiocyanophenylthio)-benzothiazole l-lydrogen chloride is introduced for 90 minutes, with cooling, into a mixture of 12.9 g of 2-(4'- aminophenylthio)benzothiazole (obtained from 2-(4'- nitrophenylthio)-benzothiazole by catalytic hydrogenation, see Example 6) and 15.4 g of bis-(diethyl)thiocarbamoyl-disulphide in 250 ml of anhydrous chlorobenzene. Stirring is afterwards carried out for 4 /2 hours with refluxing, animal charcoal is added and filtration performed hot. The filtrate is concentrated by evapora- -Contmued Melting Compounds: point in C 2-(4'-isothiocyanophenoxy)-benzoxazole 105 109 2-(4-chlorophenylthio)-6-isothiocyano- 98 l()4 benzoxazole 2-(4'-isothiocyanophenylthio)-6-nitro- 154 156 benzoxazole 2-(N-henzylN-methylamino)-6-isothio- 77 79 cyanobenzoxazole 2 (4-chlorobenzylthio)fi-isothiocyanol2l I23 benzoxazole 2-(4-isothiocyanobenzylthio)- benzoxazole We claim:

ll. An isothiocyanobenzimidazole compound of the formula and Y is oxygen, sulphur or Nll-l.

2. A salt of a compound according to claim ll, said salt being non-toxic to warm-blooded animals.

3. The compound of claim l which is 2-(3- isothiocyanophenoxy )-benzimidazole.

4. The compound according to claim 2 which is 2- (3 '-isothiocyanophenoxy )-benzimidazole hydrochloride.

5. The compound according to claim 11 which is 2- (4'-isothiocyanophenoxy )-benzimidazole.

6. The compound according to claim l which is 2- (3 -isothiocyanophenoxy l -methylbenzimidazole.

7. The compound according to claim 2 which is 2- (4-isothiocyanophenoxy)-benzimidazole sulphuric acid salt.

8. The compound according to claim 2 which is 2- (4-isothiocyanophnoxy l -methyl-benzimidazolehydrochloride.

9. The compound according to claim l which is 2- [4'-isothiocyanophenylthio]-benzimidazole.

10. The compound according to claim 2 which is 1- methyl-2-(p-isothiocyanophenylthio)-benzimidazolechlorohydrate.

111. The compound according to claim 1 which is 2- (4-isothiocyanobenzylthi0)-benzimidazole.

112. The compound according to claim 1 which is 2- (4-isothiocyanatophenoxy)-5- isothiocyanobenzimidazole.

13. The compound according to claim 2 which is 2- (4-chlorophenylamino)-5-isothiocyanobenzimidazole hydrochloride.

Claims

1. AN ISOTHIOCYANOBENZIMIDAZOLE COMPOUND OF THE FORMULA

2. A salt of a compound according to claim 1, said salt being non-toxic to warm-blooded animals.

3. The compound of claim 1 which is 2-(3''-isothiocyanophenoxy)-benzimidazole.

4. The compound according to claim 2 which is 2-(3''-isothiocyanophenoxy)-benzimidazole hydrochloride.

5. The compound according to claim 1 which is 2-(4''-isothiocyanophenoxy)-benzimidazole.

6. The compound according to claim 1 which is 2-(3''-isothiocyanophenoxy)-1-methyl-benzimidazole.

7. The compound according to claim 2 which is 2-(4''-isothiocyanophenoxy)-benzimidazole sulphuric acid salt.

8. The compound according to claim 2 which is 2-(4''-isothiocyanophenoxy)-1-methyl-benzimidazole-hydrochloride.

9. The compound according to claim 1 which is 2-(4''-isothiocyanophenylthio)-benzimidazole.

10. The compound according to claim 2 which is 1-methyl-2-(p-isothiocyanophenylthio)-benzimidazole-chlorohydrate.

11. The compound according to claim 1 which is 2-(4''-isothiocyanobenzylthio)-benzimidazole.

12. The compound according to claim 1 which is 2-(4''-isothiocyanatophenoxy)-5-isothiocyanobenzimidazole.

13. The compound according to claim 2 which is 2-(4''-chlorophenylamino)-5-isothiocyanobenzimidazole hydrochloride.